Description du projet
Interactions ADN-protéines: nouvelles causes de la formation du cancer?
Les interactions entre l’ADN et les protéines sont essentielles à de nombreuses fonctions biologiques, notamment la transcription et la division cellulaire. Cependant, ces interactions sont transitoires et dynamiques par nature. Les liaisons covalentes permanentes des protéines avec les molécules d’ADN – connues sous le nom de liaisons transversales ADN-protéines (DPC) – interfèrent avec le rôle physiologique de l’ADN et des protéines et entraînent une instabilité génomique. Le projet DNAProteinCrosslinks, financé par l’UE, étudiera le mécanisme de réparation des DPC, qui est essentiel à la viabilité des cellules et à la suppression des tumeurs. Le projet fournira des informations fondamentales sur la détection et le contrôle de la qualité des DPC dans les cellules, offrant en même temps une nouvelle perspective sur les voies à l’origine de l’instabilité génomique.
Objectif
This project aims to address the most pressing questions in the emerging field of research on DNA-protein crosslinks (DPCs) and their repair. Covalent DPCs are highly toxic DNA lesions that block virtually all chromatin processes. DPCs are induced by various exogenous and endogenous agents, but dedicated repair mechanisms were unknown. It was previously assumed that DPCs are repaired by canonical DNA repair pathways. This has changed with my recent discovery of a specific and conserved DPC repair mechanism. I established that proteases of the SPRTN family degrade the protein components of DPCs, which maintains genome stability and ensures tumour suppression. Strikingly, DPC repair by SPRTN is essential for cellular viability, which suggests that cells are constantly challenged with substantial amounts of endogenous DPCs.
I hypothesize there is an entire unexplored pathway regulating protease-based DPC repair and that DPCs are key drivers of endogenous genome instability. I will employ genetic screening approaches and develop novel functional assays to systematically define the components and working principles of this novel DNA repair pathway in mammalian cells. I will determine how DPCs are detected in a chromatin context, how different repair activities are coordinated and connected to cellular processes such as replication or transcription. Moreover, I will identify the currently elusive origins of endogenous DPCs, by investigating the essential role of the SPRTN protease.
My results will not only provide insights into an essential cellular quality-control mechanism but also unravel processes causing genomic instability in human cells. Importantly, many chemotherapeutics used in the clinic exert their cytotoxicity by inducing DPCs. My results will thus have imminent implications for human health and have the potential to reveal novel drug target candidates for combination anti-cancer therapy.
Champ scientifique
Mots‑clés
Programme(s)
Thème(s)
Régime de financement
ERC-STG - Starting GrantInstitution d’accueil
80539 Muenchen
Allemagne